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Updates on Urology
Pharmacology:
Focus on Antibiotics
Kristen Nichols, PharmD, BCPS (AQ-ID), BCPPS
Assistant Professor, Pharmacy Practice
Butler University College of Pharmacy and Health Sciences
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2
I could talk about antibiotic use and resistance ALL day
Evidence-based = challenging
[MANY studies needed]
DISCLAIMERS…
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3
• Design and monitor a therapeutic regimen for a patient with a urinary tract infection caused by a multi-drug resistant organism
• Describe ways to prevent or delay the development of antibiotic resistance
• Compare risks and benefits of continuous antibiotic prophylaxis
• Discuss strategies for optimal surgical prophylaxis in urologic procedures
Objectives
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Kevin: a 5 year old with a complex urologic tract
4
History of multiple UTIs
Daily cephalexin prophylaxis at home
Culture obtained
Cloudy urine
Increased accidents
Fever
Empiric therapy
Cefixime
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5
Extended-spectrum beta-lactamase producer
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Antimicrobial Resistance
6
• Urinary tract abnormalities (& bladder dysfunction)
• 1 course of antibiotics in past 6 months
• Antibiotic prophylaxis use
• Recent hospitalization
Predictors of antimicrobial
resistance in UTIs
• Typically resistant to ≥ 1 organism from ≥ 3 drug classes
• Resistance genes are often paired
Multi-Drug Resistant
Organism (MDRO)
• 5-10% of UTIs in children
• Force use of second-line drugs
• Increase hospital length of stay and cost
ESBL-producing organisms
Shaikh N et al. J Pediatr. 2016;171:116-121. Wragg R et al. J Pediatr Surg. 2017;52:286-288.
Nieminen O et al. Acta Paediatrica. 2016;106:327-333.
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Antimicrobial choice
7
Empiric
• Use local antibiogramdata
• Urinary isolates from your population ideal
• Consider risk factors
• Previous patient cultures
Directed
• Use susceptibility panel
• Most narrow option
• Least likely to cause collateral damage
• Patient-specific factors
• Allergies
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Big Names in Resistance
8
Extended Spectrum Beta-Lactamase (ESBL)
• Hydrolyzes extended-spectrum penicillins & cephalosporins
• Most common in E. coli and K. pneumoniae
• Beta-lactamase inhibitors like tazobactam retain activity
AmpC Beta-Lactamase
• Most common in Enterobacter cloacae, Serratia marcescens, Morganella morganii
• Hydrolyzes piperacillin/tazobactam but not cefepime
Carbapenem-Resistant Enterobacteriaceae (CRE) & Klebsiella Pneumoniae Carbapenemase (KPC)
• Hydrolyzes carbapenems
• Often resistant to other classes as well
Hsu AJ, Tamma PD. Clin Infect Dis. 2014;58:1439-48.
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Extended Spectrum Beta-Lactamases
Treatment Options
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10
Extended-spectrum beta-lactamase producer
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Oral: Nitrofurantoin
11
• Only for cystitis
– Doesn’t reach adequate tissue concentrations for pyelonephritis
– Not for use if CrCl < 30 mL/min
• Precautions:
– May lead to hemolytic anemia in patients who are G6PD deficient
– Not for <1 month of age
• Liquid dosage form has to be given every 6 hours for treatment
• Macrocrystal/monohydrate formulation can be given twice daily
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• Only for treatment of “uncomplicated” cystitis
– Due to concentrations reached with oral therapy
• Spectra of activity:
– Enterobacteriaceae
– Pseudomonas
– MRSA & VRE
• Available as a powder packet (3 grams)
• Well tolerated
– Potential mild GI distress
• Not FDA-approved in children
• Suggested dosing:
– <18 yo: 2 grams x 1
– > 18 yo: 3 grams x 1
– Principi et al used 1 gram for <1 year old
• Has been used every other day x 6 – 21 days for complicated UTI in adults
Oral: Fosfomycin Tromethamine
12Hsu AJ et al. Clin Infect Dis. 2014;58:1439-48. Reffert JL et al. Pharmacotherapy. 2014:34:845-857.Principi N et al. Chemotherapy. 1990;36:41-45.
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Oral: Fluoroquinolones
13
• Well-absorbed (80-100%)
• Save for when absolutely necessary
– Many adverse effects, some serious
– Collateral damage – rapid development of resistance
• Dose at higher end of range to avoid resistance
– Renal adjustments needed
• Delafloxacin: new FQ (not yet FDA approved or studied in < 18 years)
Ciprofloxacin LevofloxacinMoxifloxacin: NOT for UTIs
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Intravenous: Carbapenems
14
• Typically considered drugs of choice for ESBL-producing organisms
• Overuse can result in carbapenem-resistant Enterobacteriaceae
• Drug interaction: meropenem and valproic acid
• Very broad spectrum – gram-negatives, gram-positives, & anaerobes
Meropenem Ertapenem DoripenemImipenem/
cilastatin
Hsu AJ et al. Clin Infect Dis. 2014;58:1439-48.
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Intravenous: Piperacillin/Tazobactam
15
• 80-90% of isolates will demonstrate in vitro susceptibility
• Controversial in the treatment of ESBL+ infections
– Less effective for invasive infections
– Majority of infections in studies demonstrating success were UTI or biliary tract infections
• High urine concentrations
• Limited data using in children
Hsu AJ et al. Clin Infect Dis. 2014;58:1439-48.
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• Often resistant in ESBL+ infections
• Not used alone for bacteremia
– Potential increased mortality
– Development of resistance
• Ok alone for uncomplicated UTI
– Very high urine concentrations
• IV only (no oral)
• Once-daily dosing
– Optimizes pharmacokinetic and pharmacodynamic properties
• Monitoring:
– Nephrotoxicity
– Ototoxicity with repeated or prolonged courses
Intravenous: Aminoglycosides
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Intravenous: Cefoxitin (?)
17
• Will be “susceptible” on the in vitro susceptibility panel
– Possibly related to inoculum effect?
• VERY limited data for use in ESBL+ infections
– None in pediatrics
• If using for carbapenem-sparing:
– Aggressive dose
– UTI only (or potentially when source control is very good and severity is low)
– Resistance less like to develop in future with E. coli as compared to K. pneumoniae
– Close monitoring
Kerneis S et al. Infectious Diseases. 2015;47:789-95. Guet-Rivellet H et al. Antimicrob Agent Chemother. 2014;58:4899-4901.
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Intravesicular: Sodium oxychlorosene
18
• OTC as Clorpactin WCS-90
• Topical antiseptic – bladder irrigation
– 0.025 – 0.02%
• Typically 2 x 10 minute instillations BID
– For 3 days
• Can cause some burning
• Has also been used for prophylaxis
• Not studied or FDA-approved in children
Broad Spectrum Antimicrobial for Topical Application: Clorpactin WCS-90. Guardian Laboratories. Hauppauge, New York. August 2000. Clorpactin WCS-90. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Accessed August 31, 2017
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Kevin: a 5 year old with a complex urologic tract
19
History of multiple UTIs
Daily cephalexin prophylaxis at home
Culture obtained
Cloudy urine
Increased accidents
Fever
Empiric therapy
Cefixime
• Ciprofloxacin 15 mg/kg PO Q12H
• Fosfomycin a reasonable option
• If bacteremic or upper tract involved IV piperacillin/tazobactam
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10 year-old with a KPC-UTI and Bacteremia
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Klebsiella pneumoniae Carbapenemase
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• NO beta-lactams
• Fosfomycin (cystitis only)
• Colistin
– Dosing guidance limited
• Combination options:
– Double carbapenem
• Meropenem + ertapenem
• Recent study demonstrated improved mortality vs tigecycline, colistin, or gentamicin
– Extended-infusion meropenem (3-4 hours) + aminoglycoside, fluoroquinolone, or colistin
De Pascale G et al. Critical Care. 2017;21:173. Hsu AJ et al. Clin Infect Dis. 2014;58:1439-48.
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Ceftazidime/
avibactam
• Approved in adults 2015
• Ceftazidime is well-studied in children
• Avibactam isn’t
– Most BLI aren’t
• Active against ESBLs and many carbapenemases
– No Ambler class B
Meropenem/
vaborbactam
• Approved in adults last week
– Complicated UTI
• Not yet available
• Will be reserved for patients/isolate in true need
Newer Therapies
22Zasowski EJ et al. Pharmacotherapy. 2015;35:755-770. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573955.htm
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10 year-old with a KPC-UTI and Bacteremia
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Preventing Development of Resistance:
Antibiotics are a shared resource – and becoming a
scarce resource
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Strategies to Save our Antibiotics
25
1. Use antibiotics only when necessary
a) Don’t treat asymptomatic bacteruria
b) Narrowest spectrum possible
2. Avoid high-impact agents (FQs, cephalosporins) when possible
3. Limit to minimum effective duration
4. Optimize doses based on PK/PD
5. Use prophylaxis wisely
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Cephalosporins
26
• Association with :
– Vancomycin-resistant Enterococci (VRE)
– ESBL-producing K. pneumoniae
– Multidrug resistant Acinetobacter
– Clostridium difficile infections
• Most data with 3rd generation cephalosporins
– Ceftriaxone, cefotaxime (IV)
– Cefdinir, cefixime, (oral)
– Narrower options like cephalexin likely have less impact
Paterson DL. Clin Infect Dis. 2004;38:s341-5.
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Fluoroquinolones
27
• Risks to patient
– New FDA Boxed Warning
• Disabling and potentially irreversible adverse effects
• Neuropsychiatric effects– CNS, peripheral neuropathy
• Fluoroquinolone-Associated Disability
– Musculoskeletal adverse effects
• Tendinopathy, arthritis, arthralgia, gait abnormality
• Risks to resistance & collateral damage
– Resistance to fluoroquinolones develops more rapidly than with other antibiotic classes
– Association with:
Jackson MA et al. Pediatrics. 2016;138(5):e1-e13.Kaur K et al. J Community Support Onc. 2016;14(2):54-65.
ESBLs MRSACarbapenem-
resistant Pseudomonas
C. diff Candida VRE
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Rodvolt, KA et al. Pharmacotherapy 2001; 21:233S–252S
Probability of gram-negative bacteria remaining susceptible as a function of duration of treatment days
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Overview of Prophylaxis
29
Makes a lot of sense
• Historically a good alternative to surgery
• Association between UTI & scarring
• Some evidence does indicate decreased UTIs and renal scarring
• Makes us feel like we’re doing something
Some serious downsides
• Does it truly prevent UTIs or renal scarring? (mixed results & varied populations)
• Increase in resistance due to impact on bowel and periurethral flora
• Adverse effects to patient
• Can’t prevent everything
Brandstrom P et al. Pediatr Nephrol. 2015;30:425-432.
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Antibiotic Prophylaxis
Anti-infectives are the only drugs where use in one patient can impact their
efficacy in others
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UTI Prophylaxis in VUR
31
• Studies that demonstrate benefit of prophylaxis
– PRIVENT trial: modest benefit (19% to 13%)
– Swedish reflux trial: prevented renal damage
• Studies that demonstrate lack of benefit or harm
– Clarke et al: increased infections in children who catheterize (CIC)
– Garin et al: more recurrences in antibiotic group vs prophylaxis group
– 2011 AAP UTI Guidelines: meta-analysis of 6 studies
– Hari et al: prophylaxis group had an increased risk of developing UTI; similar scarring; increased resistance
Brandstrom P et al. Pediatr Nephrol. 2015;30:425-432.Hari P et al. Pediatr Nephrol. 2015;30:479-486.
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RIVUR Study
32
• 607-patient randomized placebo-controlled study
• >90% females; median age 12 mos; mostly grade II & III
• Results:
– Febrile or symptomatic UTI recurrence reduced by half (HR 0.5; 95% CI 0.34-0.74)
• 14.8% vs 27.4% (missing data excluded)
• 16 antibiotic patient-years to prevent 1 case
– Renal scarring was not impacted (11.9% vs 10.2%)
– Resistance to TMP/SMX: 63% vs 19% • Of patients with UTI recurrences caused by E.coli
– Effect lost when no initial febrile episode or bowel/bladder dysfunction
• See figure 3 in article
RIVUR trial investigators. N Engl J Med. 2014;370(25):2367-76.
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The Problem with Data
33
• Prophylaxis should be decided on a patient-by-patient basis
– Slant towards minimization
• Considerations:
– Potential risk stratification?
– Patients who are difficult to diagnose or present with severe UTI
– Febrile on initial presentation
– Degree of reflux/dilatation
– Presence of bladder or bowel dysfunction
The “holy grail” study is unlikely to be
completed
Studied populations
vary drastically
Adherence to therapy
should be considered
Bacteria are constantly evolving
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Prophylaxis in Hydronephrosis
34
Easterbrook et al: Updated Systematic Review 2017
11 studies 3909 patients; 10 non-randomized
Significant heterogeneity
UTI rates: 9.9% in prophylaxis group vs 7.5% in no-prophylaxis group
Easterbrook B et al. Can Urol Assoc J. 2017;11:s3-11.
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Surgical Prophylaxis
35
Optimal peri-operative prophylaxis
Prevents infection & therefore antibiotic use
Avoids antibiotic exposure when unnecessary
Chan KH et al. J Urol. 2017;197:944-950. Sandora TJ et al. JAMA Pediatr. 2016;170:570.
Pediatric Health Information System Database Studies
• Sandora et al: evaluated variability in prophylaxis across all surgical procedures 2010 - 2013
– Urologic procedures had greatest variability
• Chan et al: evaluated variability in prophylaxis in clean and clean-contaminated urologic procedures 2012 - 2014
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36
Chan KH et al. J Urol. 2017;197:944-950.
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37
Chan KH et al. J Urol. 2017;197:944-950.
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Prophylaxis in Outpatient Circumcision
38
• Evaluated 84,226 outpatient circumcisions (>30 days to <18 years) in PHIS database
• Surgical prophylaxis did not prevent:
– Surgical site infection (0.1% vs 0.2%)
– Penile reoperation (0.01% vs 0.04%)
– Hospital visit (5.5% vs 5.5%)
• Surgical prophylaxis did result in:
– More allergic reaction (3.5% vs 2.9%, p<0.05)
– More hospital visits (multivariate analysis)
Chan KH et al. J Pediatr Urol. 2017;13:205.e1-205.e6.
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Surgical Prophylaxis in Hypospadias Repair
39
• ~76% of pediatric urologists reported using antibiotic surgical site infection (SSI) prophylaxis for stented hypospadias repair
• Overall very low SSI rate
Smith J et al. Can J Urol. 2017;24(2):8765-8769.
224 patients retrospectively
evaluated
Pre-op antibiotics vs none
(SMX/TMP while stent in place)
No difference in:
SSI (1 vs 0)
Complications (5.2 vs 6.7%)
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Key Takeaway Points
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• Resistant isolates often require use of less-studied, more harmful, or IV-only medications
• There are a variety of strategies to help delay development of resistance, including avoiding use of FQs, optimizing doses, and minimizing duration
• Continuous antibiotic prophylaxis should be limited to a small population at highest risk
• Risks and benefits of prophylaxis should be considered
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Updates on Urology
Pharmacology:
Focus on AntibioticsKristen Nichols, PharmD, BCPS (AQ-ID), BCPPS
Assistant Professor, Pharmacy Practice
Butler University College of Pharmacy and Health Sciences
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More Good Articles
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• Hsu J, Tamma PD. Treatment of multidrug-resistant gram-negative infections in children. Clin Infect Dis. 2014;58(10):1439-48.
• Greenfield SP et al. Vesicoureteral reflux and antibiotic prophylaxis: why cohorts and methodologies matter. J Urol. 2016;196:1238-43.